ABSTRACT The number of newborns that develop the constellation of drug withdrawal symptoms or Neonatal Abstinence Syndrome (NAS) in the US has increased to epidemic proportions. The pharmacologic treatment of NAS with morphine or methadone is highly concerning as it corresponds with a timeframe of rapid postnatal brain devel- opment. The negative effects of opioids on the developing brain include decreased neurogenesis, synaptogen- esis, and corticogenesis, decreased brain size, and decreased brain volumes in older children with prenatal opiate exposure. Furthermore, response of neonates to treatment is highly variable and limited pharmaco- genetic and metabolic activity data, which can be used to optimize therapy in this population, pose additional challenges in using any drug to treat NAS. Collectively, these issues present a critical need to evaluate and optimize the use of a non-opioid drug for treatment of NAS. The long term goals of our research is to establish the best pharmacological treatment for NAS and determine how pharmacologic treatment of NAS affects long- term developmental outcomes. The objective of this application is to evaluate the effectiveness of clonidine, an ?2 adrenergic receptor agonist, as a treatment for neonates with NAS, in a randomized clinical trial. Our cen- tral hypothesis is that clonidine will effectively treat drug withdrawal manifestations in neonates. Preliminary clinical evidence supports this hypothesis. Clonidine has previously been reported by us and others as a single drug therapy for NAS in small number of infants with relief of withdrawal symptoms and as an effective adjunc- tive treatment, when giving chloral hydrate or morphine. The rationale for the proposed research is that, once we understand how clonidine can be used optimally in the clinic to treat NAS, a safe medication will be availa- ble and it could potentially minimize complications associated increased length-of-stay in the hospital, healthcare costs and the deleterious opiate assaults on the developing brain that continue with postnatal opiate administration. To test our central hypothesis and accomplish the objective of this application we plan to pur- sue the following three specific aims: 1) To determine whether the treatment of NAS with a non-opiate medica- tion, clonidine, will be more effective than morphine. 2) To determine whether treatment of NAS with clonidine will result in better early childhood outcomes than those treated with morphine. 3) To determine how infants with NAS metabolize morphine and clonidine. With respect to expected outcomes, this proposal will provide prospective evidence: a) regarding the potential of clonidine treatment to treat NAS; b) regarding how opioid and non-opioid exposure affect early childhood development; c) regarding factors that influence response to treatment. These results are expected to have an important positive impact, because they have the potential to provide fundamental information regarding the metabolic ontogeny of infants exposed to opioid drugs and, most importantly, to improve the long-term outcomes of children born to addicted mothers.